Synthesis of steroids of the 12-alkylidenepregnene



This application is a continuation-in-part of our US. application No. 711,780, filed January 29, 1958, and now abandoned.

This invention relates to the synthesis of steroids and. 1

has for its object the provision of new steroids of the eneral formula C HaY wherein the 1,2-position is saturated or double-bonded, R is lower al kylidene (preferably methylene), Y is hydrogen, hydroxy or acyloxy, and Z is hydrogen or hydroxy; a process for preparing these steroids; and new intermediates useful in said preparation.

The new 12-alkylidene steroids of this invention are prepared by interacting (A) one of the following: 12a-(lower alkyl)-1lot-hydroxyprogesteroneg 12a-(lower alkyl) A -pregnadiene-l lot-ol-3,20-dione; Hot-(lower alkyl)-11a 17a-dihydroxwprogesterone; l2a-(lower aIkyD-A -pregl'ladlfil'lfi-llOt,17c-dlJOl-3,20-dl0l'l, or a 2l-ester of one of the following steroids: l2oc-(1OW61' a1kyl)-A -pregnene-1la, 21-diol-3,20-dione; 12a(lower alkyl)-A -pregnadiene- 1 1a,21- diol-3,20-dione;12a-(lower alkyD-M-pregnene-l c, 17u,21-triol-3,20-dione; and l2a-(lower alkyl-A -pregna diene-l1a,l7a,21-triol-3,20-dione; with (B) a lower alkyl or monocyclic hydrocarbon aromatic sulfonyl halide, such as mesyl chloride and tosyl chloride, whereby the new intermediates of this invention are formed, namely the Ila-lower alkane (or monocyclic hydrocarbon aromatic) sulfonyloxy derivatives of the formula CHIY' i= W IT Patented Mar. 5, 1953 glycol in the presence of an acid catalyst, and interacting the 3,20-diketal of 90c-fl11010-1 l-ketoprogesterone or the 3,20-di-ketal of 9a-flu0ro-A -pregnadiene-3,l1,20-tnione thus formed with lithium lower alkyl (e.g., lithium methyl), thereby yielding the 3,20-diketal of l2a-lower alkyl (e.g., methyD-ll-ketoprogesterone or the 3,2-0-dike-. tad of 12a-lower alkyl (e.g methyl)-A -pregnadiene- 3,11,20-trione, respectively. The resulting diket-als are reduced by means of a reducing agent, such as lithium metal in liquid ammonia, to yield the 3,20-diketal of 12alower :alkyl-llot-hydroxyprogesterone or the 3,20-diketal of (lZzx-lO-Wl' alkyl-A -pregnadiene-11a-ol-3,20=dione, respectively, and then hydrolyzed in the usual manner, as by treatment with a dilute aqueous acid at an elevated temperature, to the desired l2a-lower alkyl-lla-hydroxyprogesterone or the 12a-lower alkyl-A -pregnadienel1mol-3,20-dione respectively. These starting materials are active progestational agents which can be administered in lieu of progesterone in the treatment of habitual abortions.

The following examples illustrate the preparation of these starting materials:

EXAMPLE A (1 Preparation of 9a-Fluor0-JI-Ktoprogesterone 3,20- Bis-Ethylene Kezal A mixture of 10 g. of 9m fluoro-l l-ketoprogesterone,

350 ml. of benzene, ml. of ethylene glycol and 200 mg.

of para-toluene-sulfonic acid monohydrate is refluxed with stirring for 72 hours. cooled to room temperature and neutralized with sodium bicarbonate solution. The phases are separated and the aqueous layer reextracted with additional amounts of benzene. The combined benzene extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude residue on crystallization from acetone-hexane yields about 11 g. of the essentially pure bis-ethylene ketal melting at about 179-182". Recrystallization of this material from methanol gives an analytical sample of the following properties: M.P. about. l80190; [(11 -25".

Analysis.Calcd for C H O F(434.53): C, 69. 0; H, 8.12. Found: C, 69.19; H, 8.18.

(2 Preparation of 12a.-Methyl-11 -Ketoprogester0ne 3,20- Bis-Ethylene Ketal A solution of 9a-fluoro-ll-ketoprogesterone 3,20-bisethylene ketal (10 g.) in benzene ml.) is treated with an ethereal solution of lithium methyl ml., 13.5 mg. of lithium metal/ml. The solution is stirred for 4 hours at room temperature and then the excess lithium methyl is decomposed by the addition of ice. Chloreform (300 ml.) is added, and the mixture is washed several times with water, dried over sodium sulfate and evaporated in vacuo. Trituration of the residue with hexane gives about 4.2 g. of 12u-methyl-11-ketop rogesterone 3,20-bis-ethylene ketal, M.P. about 135-138. A second crop of crystals (about 2.4 g., M.P. about 124- 130). is obtained on concentrating the hexane mother liquor. Crystallization from methanol gives an analytical sample melting at about l39-142, [a] -8.8 (c.0716 in CHCI Analysz'S.Calcd for C H O (4 0. 6): C, 72.50; H; 8.90. Found: c, 72.71; H, 8.90.

Similarly, by substituting an equivalent amount of lithium ethyl for the lithium methyl in the procedure of Example A2, 12oz. ethyl 11 ketoprogesterone 3,20 bisethylene ketal is'obtained. Furthermore, any diketal may be substituted for the 3,20-bis-ethylene ketal' in the pro- The reaction mixture is then cedures of Example A1, thereby yielding the corresponding 3,20-diketa1 derivative.

(3) Preparation of IZa-Methyi-IIa-Hydroxyprogesterone 3,20-Bis-Ethylene Ketal To a stirred solution of 12oc-methy1-ll-ketoprogesterone 3,20-bis-ethylene ketal (640 mg.) in 100 ml. of liquid ammonia and 20 ml. of methanol, is added 500 mg. of lithium in small pieces over 15 minutes. The liquid ammonia is allowed to evaporate at room temperature and the residue is diluted with 50 ml. of water. The precipitated solid (about 620 mg, M.P. about 193207) is collected, washed well with water and dried. Crystallization from methanol gives an analytical sample of the llahydroxy compound which melts at about 211213 C; [ab-285 (c. 1.13 in CHCl Similarly, by substituting 1 g. of 12a-ethyl-11-keto progesterone 3,20-bis-ethylene ketal for the 12a-methyl-11- keto-progesterone 3,20-bis-ethylene ketal in the procedure of Example A3, 12a-ethyl-1lot-hydroxyprogesterone 3,20- bis-ethylene-ketal is obtained.

(4) Preparation of IZa-Methyl-Ila-Hydroxyprogesterone W 241 mp 15,700); A532 2.95, 5.92, 5.99, 6.22

max.

'Analysis.-Calcd for C I-1 (344.48): C, 76.70; H, 9.36. Found: C, 76.50; H, 9.23.

Similarly, 12u-ethyl-1la-hydroxyprogesterone 3,20-bisethylene ketal can be hydrolyzed to 12a-ethyl-11a-hydroxyprogesterone.

EXAMPLE B 1 Zea-M ethyl-A -Pregnadiene-1 I et-Ol-3,20-Di0ne By substituting an equal amount of 9ot-fluoro-A -preg nadiene-3,l1,20-trione for the 9a-fluoro 11 ketoprogesterone in the process of Example A1 and following the procedure of the remaining steps of the example, 120:- methyl-A -pregnadiene-11a o1 3,20-dione is obtained. Furthermore, if lithium ethyl is substituted for lithium methyl in the thus modified process of Example A2, 12aethyl-A -pregnadiene-l1u-ol-3,20-dione is ultimately obtained.

' (2) The starting 21-esters of IZu-(IOWCI' a1kyl)-A pregnene-l1a,2l-diol-3,20-dione and l2a-(lower alkyl) A -pregnadiene-I1a,21-di0l-3,20-dione are prepared by: (a) reducing, with a reducing agent such as lithium aluminum hydride, the 3,20-diketal of 12a-(lower alkyl)-l1- ketop rogesterone and the 3,20-diketal of 12a-(lower alkyl)-A -pregnadiene-3,l1,20-trione, respectively to obtain the corresponding llfi-hydroxy-derivatives; (b) treating, the -1 lfi-hydroxy derivative with a diester of oxalic acid (e.g., a lower alkyl ester such as ethyl oxalate) in the presence of approximately one equivalent of an alkali metal alkoxide (e.g., sodium methoxide), whereby the alkali metal enolate of the ester of 21-hydroxyoxa1y1-12a- (lower alkyl)-11}3-hydroxyprogesterone and 2l-hydroxyoxalkyl-12a-(lower alkyl) A -pregnadiene-11;3-ol-3,20- dione are formed; (0) interacting the alkali metal enolate ester with a base, such as an alkali metal hydroxide, to yield a 21-oxalyl-12a-(lower aIkyD-IIB-hydroxyprogesterone and 21-oxalyl-12a-(lower alkyl)-A -pregnadiene- 11/3-ol-3,20-dione, respectively; (d) treating the oxalyl compounds thus formed with iodine in a basic medium to yield ZI-iOdO-lZu-(lOWBl' alkyl)-1lfl-hydroxy-progesterone and 21-iodo-l2a-(lower aIkyD-N -pregnadiene- 11p-ol-3,20-dione, respectively; (e) converting the 21-iodo group to a 21-acyloxy group by treatment with the desired acid salt (preferably in the presence of the free acid), thereby yielding a 2l-ester of l2a-(lower alkyl)-corticosterone and l2e-(lower alkyl)-A -pregnadiene-11B, 21- diol-3,20-dione, respectively, (1) oxidizing the 21-ester of IZOL-(IOWeI' alkyl)-corticosterone (or the 1,2-unsaturated thereof) with an oxidizing agent such as chromium tritoxide; (g) hydrolyzing the ll-keto analog thus prepared with a base such as potassium carbonate; (h) ketalizing the l2a(lower a1kyl)-1l-dehydrocorticosterone (or the 1,2 unsaturate thereof), thus obtained, with ethylene glycol; (i) reducing the 3,20-bis-ethylene ketal with a reducing agent such as lithium in ammonia; and (j) deketalizing the thus obtained 12ot-(l0W61 -alkyl)-1lqz-hydroxy compounds with a hydrolyzing agent such as a dilute aqueous acid to obtain 12a-(lower alkyD-M-preg- Ilene-1104,21 di0l-3,20-di011 or the 1,2-unsatur'ated thereof. .The'se starting materials are mineralo corticoids which are physiologically active and can be used in place of such known substances as desoxycorticosterone.

The following examples illustrate the preparation of these starting materials:

EXAMPLE C 12 a-Methyl-Corticosterone 21 -A cetate (1) Preparation 0]"12a methyl 11 3 hydroxyproges terone 3,20-bis-ethylene ketal.A solution of 1 g. of 12amethyl-ll-ketoprogesterone 3,20-bis-ethylene ketal in 50 ml. of dry tetrahydrofuran is heated under reflux with 1 g. of lithium aluminum hydride for 18 hours. Ice is added to the cooled solution to decompose excess reagent and then a saturated aqueous solution of sodium sulfate is added with stirring until the precipitated aluminum salts are formed into a slurry. The clear ether solution is decanted off and the inorganic material is Washed twice with chloroform. The combined organic extracts are dried over sodium sulfate and then evaporated in v-acuo. The residue is dissolved in 10 ml. benzene and absorbed on a column of 30 g. of alumina. Elution with benzene (900 ml.) and chloroform-benzene (1:9, 500 ml.), followed by crystallization from acetone-hexane, yields 12ccmethyl-llfi-hydroxyprogesterone 3,20-bis-ethylene ketal (about 660 mg.) melting at about 169-175". Crystallization from acetone-hexane affords an analytical sample which melts at about 177179; [a] 11.5 (c. 1.24 in CHClg);

A 241 mp (16,600); was

Analysis.Calcd for C H O (344.48): C, 76.70; H, 9.32. Found: C, 76.59; H, 9.41.

(3) Preparation of 21-eth0xy0xalyl 12a methyl-11phydr0xyprogesterone.To a solution of 7.23 g. of 12amethyl-l lfl-hydroxyprogesterone in ml. of tertiary butyl alcohol is added at 50 10 ml. of ethyl oxalate and 1.03 ml. of a 2 N methanolic solution of sodium methoxide. The mixture is stirred at room temperature for 3 hours during which time the sodium enolate of 21- ethoxyox al-yl-lZa-methyl-l1 9 hydroxyprogesterone sepa- 2.9, 5.91 (inflection); 5.95,

5 rates from solution. The material is collected, dissolved in water and the solution acidified with dilute hydrochloric acid. The precipitated 2l-ethoxyoxalyl compound is collected, washed with a little dry ether and dried in vacuo.

(4) Preparation of ZJ-oxaZyI-IZa-methyl-I]fl-hydroxy prgesler0ne.To a solution of 800 mg. of potassium hydroxide in 30 ml. of ethanol is added g. of the sodium enolate of 21 ethoXyoXaIyLIZa-methyI-Il-fl-hydroxyprm gesterone, and the mixture is stirred at room temperature under nitrogen for 8 hours. The reaction mixture is diluted with 1.5 liters of Water and then acidified with dilute hydrochloric acid. The precipitated 21-oxalyl compound is collected, washed with water and dried in vacuo.

(5) Preparation of 21Jada-l2a-mezhyl-IJfl-hyaroxyprogesterone.A suspension of 5 g. of 2l-ethoxyoxalyll2a-methyl-1lB-hydroxyprogesterone in a solution of 1.35 g. of potassium hydroxide in 50 ml. of ethanol is stirred at room temperature for 6 hours. The mixture is poured into 3 liters of water in which has been previously dissolved 48 g. of disodium hydrogen phosphate dodecahydrate. To the resultant solution is added first, dropwise with stirring, 4 g. of iodine in 200 ml. of methanol and then 3.2 g. of potassium hydroxide dissolved in the minimum quantity of Water. After allowing the solution to stand at room temperature for 16 hours, the precipitated material is collected, washed with Water and dried in vacuo. Crystallization from acetone-hexane yield-s a pure sample of the 2l-iodo compound.

(6) Preparation of l2a-methylcorticosterone 21-acerate-To a solution of 200 mg. of 21-iodo-l2a-methylllfi-hydroxyprogesterone in ml. of acetone is added 2 g. of potassium bicarbonate and 1.35 ml. of glacial acetic acid. The mixture is then refluxed for 18 hours. Water is added and the steroids are extracted with chloroform. The chloroform solution is washed with Water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane yields IZa-methylcorticosterone 21-acetate.

Similarly, by substituting l2a-methyl-A -pregnadiene- 3,11,20-trione 3,20-bis-et-hylene ketal for the IZa-methylllfl-ketoprogesterone 3,20-bis-ethylene ketal in the procedure of Example Cl and following the procedures of Example C2 through 6 the corresponding l-dehydro intermediates are formed, leading ultimately to IZa-methyl- A regnadiene-I1}8-21-diol-3,20-dione ZI-acetate. Furthermore, by substituting other 12a-(lower allry1)-l1-ketoprogesterone 3,20-bis-ethylene ketal (e.g., 12a-ethyl-11-.

ketoproge-sterone 3,20-bis-ethylene ketal) for the 12amethyl steroid in Example (31 and following the procedures of Example C2 through 6, the corresponding 12a- (lower alkyl) intermediates are formed, and the corre; sponding IZOt-(IOWCI alkyl) corticosterone 2l-acetate (e.g., IZa-ethylcorticosterone 21-acetate) are recovered; as the final products. Moreover, if another acid is sub stituted for the glacial acetic acid in Example C6, the corresponding 2l-ester is formed.

(7) Preparation of Hot-methyl 11 dehydrocorticosterone 21-ace2aze.T0 a stirred solution of 5 g. of 12amethylcortieosterone 21-acetate in 200 ml. of acetone is added chromium trioxide in 0.67 N sulfuric acid (200 mg./ml.) until a permanent brown coloration is obtained (about 5 ml. required). The solution is stirred at room temperature 30-minutes. Methanol is added to destroy the excess chromic acid and then the mixture is concentrated to about half its volume in vacuo. On adding water, the ll-ketone separates from solution. The material is collected, Washed with Water, dried and crystallized from acetone-hexane.

(8) Preparation of Hot-methyl 1] dehydrocorticosterone-To a stirred solution of 4.3 g. of 12a-methylll-dehydrocorticosterone 2'1-acetate in 50 ml. of methanol is added under nitrogen 10.5 ml. of 10% potassium carbonate solution. After stirring for one hour, the mix- 6 ture is neutralized by the addition of 1.5 ml. of glacial acetic acid. Saline solution is then added to precipitate the 12a-methyl-11-dehydrocor|ticosterone. The solid is collected, washed with Water, dried and crystallized from acetone-hexane to give 12a-methyl-1l-dehydrocorticosterone.

(9) Preparation 0 JZa-me'thyl-A -pregnene-21-0l-3,11, ZO-tfforre 3,20-bis-ethylene ketal.A mixture of 3 g. of 12a-rnethyl-1l-dehydrocorticosterone, 150 ml. of benzene, 24 ml. of ethylene glycol and 48.4 mg. of p-toluene sulfonic acid monohydrate is heated under reflux for 24 hours, the water formed during the reaction being removed azeotropically in a suitable separator. The mixture is diluted with 200 ml. of chloroform and washed successively with dilute sodium bicarbonate and Water. Evaporation in vacuo followed by crystallization of the residue from methanol yields 12a-methyl-A -pregnene-21- ol-3,ll,20-trione 3,20-bis-ethylene ketal.

(10) Preparation of 1Zea-methyl-M-pregnene-I]a,21- dz'0l-3,20-di0ne 3,20-bis-ethylene ketal.To a solution of 200 mg. of l2ix-methyl-A -pregnene-21-ol-3,l1,20-trione 3,20-bi-s-ethylene ketal in 8 ml. of methanol and 50 ml. of liquid ammonia is added over a ten minute period 160 mg. of timely out lithium. The solvent is allowed to evaporate off at room temperature (about 2 hours) and the residue is tritunated with water. The precipitated material is collected, Washed with Water and dried in vacuo. Crystallization from acetone-hexane yields 12a methyl A pregnene lla,2l diol 3,20 dione 3,20-bis-ethylene (hotel.

(11) Preparation of 12a-methyl-A pregnene-1104,21- di0l-3,2-0-dione.-A solution of mg. of IZa-methyl- A -pregnene-l la,21-diol-3,20-dione 3,20-bis-ethylene hotel in 20 ml. of methanol and 0.8 ml. of 8% sulfuric acid is refluxed for 40 minutes. Orr dilution with Water, methyl-M-pregnene-lla,21-diol-3,20-dione separates from solution. The steroid is filtered oii, washed with water and dried in vacuo.

Furthermore, if l2a-me-thyl-A -pregnadiene-l1,8,21- diol-3,20-dio-ne 2l-acetate and l2a-ethylconticosterone 2l-acetate are substituted for the IZa-methyIcortioosterone 2l-acetate in the procedure of Example C7 and the procedures of Example C8 through 11 are followed.

the corresponding l-dehydro and l2a-ethyl derivatiwes,

are obtained, respectively.

(3) The starting Zl-esters of 12a-(lower al kyl)-A pregnene-lla,17a,2l-triol3,20-diones and 12a-(lo-wer alkyl)-A -pregnadiene-1 la,17a,2l-triol-3,20-diones can be prepared from l2a-(lower al'kyl)-1l5-hydroxyprogesterones (e.g., 12a-methyl-1lfi-hydroxyprogesterone and 12aethyl-1lfi-hydroxyprogesterone) by the following series of reactions: (a) reacting the starting steroid with a di ester of oxalic acid (e.g., a lower alkyl ester such as ethyl oxalate) in the presence of at least two equiva lents of an alkali metal alkoxide (erg, sodium methoxide) whereby the diester of 2,2l-ox-alyl-12a-(lower alkyl)-1lfi-hydroxyprogesterone, as well as its alkali metal dienolate, is formed; (b) reacting the diester with ap proximately three moles of bromine per mole of steroid and an alkali metal alkoxide to yield first the 2,2l,21 tribromide derivative and then the alkyl ester of Z-bromo- 12oz (lower alkyl) A pregnadiene llfl ol 3- one-2l-oic acid; (c) debrominating the latter compound, as by treatment with zinc in an acid medium, to yield the corresponding Z-debrominated derivative; (d) treating the debrominated compound with pyrrolidine to yield 3 pyrrolidino- 12a (lower alkyl) Abilmm pregnatriene-llfl-ol-S-one-Zl-oic acid alkyl ester; (e) reducing the Zl-acid, as by treatment with lithium aluminum hydride, to yield 12a -(lo-wcr iaikyl)-A -pregnadiene-1lfi,2ldiol-3-one; (f) acylating the latter compound in the usual manner, as. by treatment with the acyl halide or acid anhydride of a suitable organic carboxylic acid, to yield the 2 1-este-r derivative; (g) reducing the ZI-ester by "2 treatment with osmium tetroxide and phenyliodosoacetate to give the 2l-esters of 12a-(lower alkyl) hydrocorti sones; (h) oxidizing the 21-esters with an oxidizing agent (e.g., chromium trioxide) to yield 2l-esters of l2ct-(lower alkyl) cortisones; (i) hydrolyzing the l2-keto compound with a base such as potassium carbonate; (1') ketalizing the 12-keto analog, thus obtained, with ethylene glycol; (k) reducing, as by treatment with an alkali metal (e.g., lithium) in liquid ammonia, to yield the corresponding lla-hydroxy derivatives; and (l) deketalizing the 110:- hydroxy derivative thus obtained by hydrolysis to give the desired 12a-(lower alkylyn -pregnene-lla,17a,2ltriol-3,20-dines. The l2a-(lo-wer alkyl)-A -pregnene- 1la,l7a,2l-triol-3,20-d-iones can then be l-dehydrogenated microbioallly by means of Bacterium cyclooxydans by the method disclosed in Us. Patent No. 2,822,318 to yield the corresponding 12a-(lower alkyl)-A -pregnadienella,17a,21-triol-3,20-diones.

These starting materials are physiologically active substances which possess gluooc-orticoid activity and can be used in place of such known steroids ashydrocortisone in the treatment of rheumatoid arthritis.

The following examples illustrate the preparation of these star-ting materials:

EXAMPLE D JZa-Methyl- -Pregnene-11 0a,] 7 0:,21 -Tri0l-3 ,2 O-Dione (1) Preparation of 2,21 diethoxyoxalyl 120a methyl llp-hydroxyprogesterone and the sodium dienolate there- 0f.To a solution of 7.2 g. of l2e-methyl-l1B-hydroxyprogesterone in 100 ml. of anhydrous tertiary butyl alcohol at 50 is added with stirring 19 ml. of ethyl oxalate and 23.3 ml. of a 2 N methanolic solution of sodium methoxide. .On stirring the mixture for 3 hours -at room temperature the sodium dienolate of 2,21-diethoxyoxalyl- 12cc methyl 11B hydroxyprogesterone separates. This material is collected, washed with a little ether and then dissolved in water. The aqueous solution is acidified with dilute hydrochloric acid whereupon 2,2l-diethoxyoxalyl 12a methyl 11B hydroxyprogesterone separates from solution. The material is collected, washed with water and dried in vacuo.

(2) Preparation of 2 bromo 124x methyl M pregnadiene-I1 8-0l-3-0ne-21-0ic acid methyl ester.To a stirred mixture of 8.1 g. of 2,21-diethoxyoxalyl-12amethyl-1lfi-hydroxyprogesterone and 5.9 g. of anhydrous potassium acetate in 140 ml. of methanol is added at 0, 10% wt/v. of bromine in methanol over a period of 30 minutes until the bromine is no longer decolorized immediately (about 74 ml. of bromine solution required). 50 mg. of phenol is added and the solution of the 2,21,21-tribromo compound is treated with 67 ml. of 1.5 N methanolic sodium methoxide. The mixture is heated at 80 for minutes, cooled and diluted with iced water. The precipitated 2-br0mo compound is collected, washed with water and dried in vacuo.

(3) Preparation of IZa-methyl-A -pregnadiene- 11B-ol-3-0ne-2Loic acid methyl ester.- A mixture of 5 g. of 2-bromo-l2a-methyl-A -pregnadiene-11,8-01-3- one-21-oic acid methyl ester and 5 g. of zinc in 100 ml. of benzene, 50 ml. of methanol and ml. of acetic acid is stirred at room temperature for 4 hours. The inorganic material is filtered off and washed with 300 ml. of benzene. The mother liquors from the reaction are diluted with water and extracted with benzene. The combined benzene extracts are washed successively with water, dilute aqueous sodium bicarbonate and Water, then dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization from acetone-hexane gives 12amethyl A pregnadiene 11B o1 3 one 21- oic acid methyl ester.

(4) Preparation of 3-pyrr0lidin0-l ZametltylA pregnatriene-1l18-0l-3-0ne-21-0ic acid methyl ester.--To a refluxing solution of 3 g. of Z-bIOmO-IZoz-HlthYl- A -pregnadiene-11B-ol-3-one-2l-oic acid methyl ester in 35 ml. of methanol is added 3.5 ml. of pyrrolidine under nitrogen, the solution then being heated for an additional 3 minutes. Crystals of the 3-pyrrolidino derivative separate from solution. These are collected, washed with a little cold methanol and dried in vacuo.

(5) Preparation of JZa-methyl-A -pregnadiene- 11B-Z1-di0l-3-0ne.A solution of 2.8 g. of 3-pyrrolidino- 12cc methyl A -pregnatriene-llfl-ol-3-one-2l-oic acid methyl ester in ml. of anhydrous tetrahydrofuran is stirred with 2 g. of lithium aluminum hydride for 1 hour at room temperature. The reaction mixture is cooled and the excess reagent is decomposed by the careful addition of methanol. The reaction mixture is then refluxed with an acetate buffer comprising 40 ml. of methanol, 4 ml. of water, 3.2 ml. of acetic acid and 3.2 g. of sodium acetate. Water is added and the steroids are extracted with chloroform, the chloroform extract then being washed with water, dilute aqueous sodium bicarbonate and water. Evaporation of the solvent in vacuo followed by crystallization of the residue from acetone-hexane yields the diol.

(6) Preparation 0 l2oi-methyl-A -pregnadiene- 115,21-diol-3-one 21 -acetate.-A solution of 2 g. of 12amethyl-A -pregnadiene-l1/3-21-diol-3-one in 10 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then diluted with iced water and the precipitated solid collected and dried in vacuo. Crystallization from aceton-hexane yields a pure sample of the 21-acetate.

(7) Preparation of 12a-mezhylhydrocortisone 21-acetate.To a solution of 386 mg. of 12a-methyl-A pregnadiene-l1B-2l-diol-3-one 21-acetate in 15 ml. of anhydrous tertiary butyl alcohol is added first 322 mg. of phenyliodoacetate in 0.3 ml. of pyridine and then 15 mg. of osmium tetroxide. The mixture is allowed to stand at room temperature for 18 hours in the absence of light. The mixture is then stirred for 2 /2 hours with 17 ml. of Water, 20 ml. of benzene, 1.8 g. of sodium sulfite and 1.8 g. of sodium bicarbonate. The inorganic material is'filtered off and washed several times with chloroform. The aqueous mother liquor is extracted with chloroform. The combined chloroform extracts are then washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane yields IZa-methylhydrocortisone 21- acetate.

Similarly, by substituting other 12a-(lower alkyD-llflhydroxy-progesterones (e.g., 12a-ethyl-11B-hydroxyprogesterone) for the IZa-methyl steroid in Example D1 and following the procedures of Examples D2 through 7 the corresponding l2u-(lower alkyl) intermediates are formed and the corresponding l2ot-(lower alkyl) hydrocorti-sone 2l-acetate (e.g., 12a-ethylhydrocortisone 21- acetate) are recovered.

(8) Preparation of IZa-methylcortisOne 21-acetate.- To a stirred solution of 5 g. of 12a-methylhydrocortisone 21-acetate in 200 ml. of acetone is added chromium trioxide in 0.67 N sulfuric acid (200 mg./ml.) until a permanent brown coloration is obtained (about 5 ml. required). The solution is stirred at room temperature 30 minutes. Methanol is added to destroy the excess chromic acid and then the mixture is concentrated to about half its volume in vacuo. On adding water, the ll-ketone separates from solution. The material is collected, washed with water, dried and crystallized from acetone-hexane.

(9) Preparation of 12a-methylc0rtis0ne.-To a stirred solution of 4.3 g. of IZa-methylcortisone 21-acetate in 50 ml. of methanol is added under nitrogen, 10.5 ml. of 10% potassium carbonate solution. After stirring for one hour, the mixture is neutralized by the addition of 1.5 ml. of glacial acetic acid. Saline solution is then added to precipitate the 12a-methylcortisone. The solid is collected, washed with water, dried and crystallized from acetone-hexane to give l2a-methylcortisone.

Preparation of ZZOz-methyI-M-pregnene-I70:,21- dial-3,11,20-trione 3,20-bis ethylene ketall--A mixture of 3 g. of l2a-methylcortisone, 150 ml. of benzene, 24 ml. of ethylene glycol and 48.4 mg. of p-toluene sulionic acid monohydrate is heated under reflux for 24 hours, the water formed during the reaction being removed azeotropically in a suitable separator. The mixture. is diluted with 200 ml. of chloroform and Washed successively with dilute sodium bicarbonate and water. Evaporation in vacuo followed by crystallization of the residue from methanol yields lZa-methyl-M-pregnened7a,2l-diol-3,ll, -trione 3,20-bis-ethylene ketal.

(11) Preparation of 12a-methyl-Aipregnene-ll0a,]7a, 21-tri0l-3,20-dione 3,20-bis-ethylene ketal. -To a solution of 200 mg. of 12a-methyl-A -pregnene-l7a,21-diol- 3,11,20-trione 3,20-bis-ethylene ketal in 8 ml. of methanol and ml. of liquid ammonia is added over a ten minute period, 160 mg. of finely cut lithium. The solvent is allowed to evaporate of at room temperature (about 2 hours) and the residue is titurated with water. The precipitated material is collected, washed with Water and dried in vacuo. Crystallization from acetone-hexane yields l2a-methyl-A -pregnene lla,l7a,2l triol 3,20- dione 3,20 bis-ethylene ketal.

(12) Preparation of J2a-methyl-A -pregnene-11a,17a,

2 1-tri0l-3,20-di0ne.-A solution of 100 mg. of 12a methyl-A -pregnene-11a,17a,21-triol-3,20-dione 3,20-bisethylene ketal in 20 ml. of methanol and 0.8 ml. of 8% sulfuric acid is refluxed for 40 minutes. On dilution with water, IZa-methyIeA regnene-l la,17zx,21-tri0l3, 20-dione separates from solution. The steroid is filtered off, washed with water and dried in vacuo.

Similarly, if 12a-ethylhydrocortisone acetate is substituted for the l2a-methylhydrocortisone acetate in the procedure of Example D8 and the procedures of Examples D9 through 12 are followed, the corresponding 12aethyl derivative is obtained.

EXAMPLE E 1 2a-Methyl-A -PregnadieneJ1a,] 7a,21-Tri0l-3,20-Di0ne Following the procedure of Example 1 of US. Patent No. 2,822,318 but substituting 12ot-methyl-A -pregnenella,17a,2l-triol-l3,20-dione for the. lla-hydroxyprogesterone, IZa-methyl A pregnadiene-lla,l7a,2l-triol-3, ZO-dione is obtained.

Similarly, other 12a-( lower .alkyl) A -pregnene-l 1oz, 17a, 2l-triol-3,20-diones, such as 12a-ethyl-A -pregnene-11a, l7a,2l-triol-3,20-dione, are converted to their respective l-dehydro derivatives.

(4) The 12a (lower :alkyl) lla,l7a dihydroxyprogest erone, and 12a (lower alkyl) A -pregnadiene-lla, l7a-diol-3,20-dione reactants can be prepared by interacting a 2l-alkane sulfonic acid ester (e.g., mesyl and ethanesulfonyl) of a Hay-(lower alkyl)hydrocortisone (e .g., l2u-methylhydrocortisone or 12a-ethylhydrocortisone)or l2a-(lower alkyl) prednisolone (e.g., 12a-methyl prednisolone) with an alkali metal iodide (e.g., sodium iodide), preferably at an elevated temperature in an organic solvent for the steriod reactant, thereby yielding the corresponding 2l-iodo derivatives [i.e. a ZI-iOdO-lZa- (lower alkyl)-1l 3-l7a-dihydroxyprogesterone and a 21- iodo-l2a-(lower .alkyl)-A -pregnadiene-l113,12a-dio1 3, 20-dione]. The 21-iodo compounds thus formed are then treated with an alkali metal bisulfite (e.g. sodium bisul fite) to deiodate the intermediate thereby forming 12oz- (lower alkyl)-11,6,17a-dihydroxyprogesterones. The 115- hy-droxy steriods thus formed are then oxidized in the usual manner, as by treatment with a hexavalent chromic compound (e.g., chromium trioxide) to yield the corresponding ll-lceto derivatives [e.g., a Hot-(lower alkyl)-l1-ketol7a-hydroxyprogesterone and a Hot-(lower ialkyl)-A pregnadiene-17a-ol-3,l1,20-trione]. The ll-keto com- 1 0. pounds are then ketalized; as by treatment with a dihydric alcohol (cg. ethylene glycol) to yield the corresponding 3,20-dilcetal derivatives, which in turn are reduced, .as by treatment with an alkali metal (e.g., lithium) in liquid ammonia,to yield the corresponding lla-hydroxy derivatives. These l-la-hydroxy steriods can then be hydrolyzed, as by treatment in :a suitable solvent such as methanol with a dilute aqueous acid at an elevated temperature, to, yield l2 lower \alkyl) -A -pregnene-l1a,17a-diol-3,20 diones and l2 a-(lower =alkyl)-A -pregnadiene-lla,17a dio1-3, 2.0-diones. These starting materials are physiologically active pr-ogestational agents which can be used in lieu of such known substances as progesterone in treatment of habitual abortion.

The following examples illustrate the preparation of these starting materials:

EXAMPLE F JZa-Methyl-N-Pregnene-J1 0a,] 7 oc-Di0l3,20-D ione (1) Preparation of 12a-methyllzydr0c0rtis0ne.--To a stirred solution of 304 mg. of IZa-methylhydrocortisone ZI-acetate in 18 ml. of methanol is added under nitrogen 3.6ml. of 10% potassium carbonate solution. After stirring for 30 minutes the reaction mixture is neutralized by the addition of 0.6 ml. of glacial acetic acid. On dilution with saline solution, l2a-methylhydrocortisone separates from-solution. The material is filtered off, washed successively with water and a little ice-cold methanol and then dried in vacuo.

(2) Preparation of l2a-methylhydrocorlisone 21 -mesylale. To a solution of 174 mg. of l2a-methylhydrocortisone in 4 ml. of anhydrous pyridine is added, at 0, 0.15 ml. of methane sulfonyl chloride. in 1 ml. of chloroform.

, The reaction is left for three hours. at 0. Dilution with iced water precipitates l2a-methylhydrocortisone 21- mesylate.

('3) Preparation of 21 -i0d0-12a-methyl-11,B,1 7a-dihydroxyprogesterone.--A mixture of 200 mg. of 1206-Il'l5fl1y1- hydrocortisone Zl-mesylate and 500 mg. of sodium iodide in 10 ml. of acetone is heated under reflux for 15 minutes. The reaction mixture is then diluted with Water, the precipitated solid collected, washed with water and dried in vacuo. Crystallization from acetone-hexane yields a pure sample of the 2 -1 a-iodo compound.

4) Preparation of JZa-InethyLJ15,17a-dihydr xypra gester0ne.--To a solution of 127 mg. of 21-iodo-l2czmethyl-ll,5,l7cx-dihydroxyprogesterone in 1.5 ml. of dioxane is added at l. 5 ,ml. of 5% aqueous sodium bisulfite, the reaction mixture then-being heated for 30 minutes. The solution is cooled, water added and the steroids extracted with chloroform. The chloroform extract is-washedwith water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization from acetonehexane yields a sample of12u-methyl-4-pregnene-11B, l7adiol-3,20-di0ne.

Similarly, by substituting other l2a-(lower alkyl)hydrocortiso ne 2l -acetate s (e .g., l2 -ethylhydrocortisone 21- acetate) for the H -methyl steriod in Example F1 and following the procedures of F2 through 4, the correspond- DEQ I-iOClO-IZct-(IQWQI alkyl) intermediates are formed and the corresponding 12a-(lower alkyl)-1l,8,l7u-dihydroxyprogesterones (e.g., IZa-ethyl-l1,3,l7a-dihydroXyprogesterone) are recovered as, the final products.

(5-) Preparation of JZa-meIhyI-II-ket0-17a-hydr0xyprogester0ne.-To a stirred solution of 5 g. of IZa-methyl- 11 8,l7wdihydroxyprogesterone in 200 ml. of acetone is added chromium trioxide in 0.67 N sulfuric acid (200 mg./ ml.) until a permanent brown coloration is obtained (about 5' ml. required). The solution is stirred at room temperature 30 minutes. Methanol is added to destroy the excess chromic acid and then the mixture is concentrated to about half its volume in vacuo. On adding Water, the ll-ketone separates from solution. The material 11 is collected, Washed with Water, dried and crystallized from acetone-hexane.

(6) Preparation of IZoc-methyl A pregnene-l7a-ol- 3,11,20-trz'0ne 3,20-bis'ethylene ketal.A mixture of 3 g. of l2a-methyl-1l-keto-l7u-hydroxyprogesterone, 150 ml. of benzene, 24 ml. of ethylene glycol and 48.4 mg. of p-toluene sulfonic acid monohydrate is heated under reflux for 24 hours, the water formed during the reaction being removed azeotropically in a suitable separator. The mixture is diluted with 200 ml. of chloroform and washed successively with dilute sodium bicarbonate and water. Evaporation in vacuo followed by crystallization of the residue from methanol yields 12a-methyl-A -preg nene-17a-ol-3,11,20-trione 3,20-bis-ethylene ketal.

(7) Preparation of J2a-methyl-A -pregnene-lla,17adiol-3,20-dine 3,20-bz's-ethylene ketal.To a solution of 200 mg. of 12a-methyl-A -pregnene-17a-diol-3,1l,20-tri one 3,20-bis-ethylene ketal in 8 ml. of methanol and 50 ml. of liquid ammonia is added over a ten minute period, 160 mg. of finely cut lithium. The solvent is allowed to evaporate off at room temperature (about 2 'hours) and the residue is triturated with'water. The precipitated material is collected, washed with water and dried in vacuo. Crystallization from acetone-hexane yields 12amethyl-M-pregnene-l 1a,17a-diol-3,20-dione 3 ,20-bis-ethylene ketal.

(8) Preparation of l2a-methyl-M-pregrzene-I1a,]7adi0l-3,20-di0ne.--A solution of 100 mg. of l2m-methyl- A -pregnene-1la,17a-diol-3,20-dione 3,20-bis-ethylene ketal in 20 ml. of methanol and 0.8 ml. of 8% sulfuric acid is refluxed for 40 minutes. On dilution with water, 12amethyl-M-pregnene-l1a,17a diol 3,20 dione separates from solution. The steroid is filtered 01f, washed with water and dried in vacuo.

Similarly, if 12rx-ethyl-11B,17a-dihydroxyprogesterone is substituted for the IZa-methyl-l l,B,l7a-dihydroxypro gesterone in the procedure of Example F5 and the procedures of Example F6 through 8 are followed, the corresponding l2a-ethyl derivatives are obtained respectively.

EXAMPLE G 12 a-Methyl-A -Pregnadiene-J 1 oz,17ot-Dl'0l-3,20-Di0ne (1) Preparation of l2ot-methylprednisolone.Following the procedure of Example 1 of U.S. Patent No. 2,822,- 318 but substituting 12oc-methylhydrocortisone for the lla-hydroxyprogesterone, 12oc-methylprednisolone is obtained.

Similarly, other IZa-(IOWSI alkyl)hydrocortisones, such as l2ot-ethylhydrocortisone are converted to their respective l-dehydro derivatives.

(2) Preparation of 12a-methyl-A -pregnadiene-l1a, 17a-diol-3,20-diorze.Following the procedure of Example F2 through 8, but substituting 12a-methylprednisolone for the 12a-methylhydrocortisone in the procedure of Example F2, lZa-methyl-A -pregnadiene-11a,17a-diol-3,20- dione is obtained.

Similarly, other 12a-(lower alkyl) prednisolones, such as 12a-ethylprednisolone are converted to their corresponding (lower alkyl)-A -pregnadiene-11a,17a-diol-3, 20-dione derivatives.

The intermediate Ila-lower alkane (or monocyclic hydrocarbon aromatic) sulfonyloxy derivatives are then treated with a salt of a strong base and weak acid (e.g. sodium acetate) in the presence of a weak acid (e.g., acetic acid) whereby the alkane (or monocyclic hydrocarbon aromatic) sulfonic acid is split off to give the desired 12-alkylidene final products. If a 21-ester is employed as the starting material and a free 21-hydroxyl compound is desired, the steroid may be hydrolyzed in the usual manner to yield a free 21-hydroxyl steroid.

The 12-alkylidene steroids of this invention are physiologically active substances which possess progestational activity. Hence, these steroids can be used in lieu of known progestational steriods, such as progesterone in the treatment of habitual abortion, being formulated for such 12 administration in the same type of parenteral preparations as progesterone, for example, with concentration and/or dosage based on the activity of the particular compound. The following examples are illustrative of the invention (all temperatures being in centrigrade):

EXAMPLE 1 l 2 zx-M ethyl-1 1 a-Hydroxyprogesterone 1 1 oc-M esy late A solution of 1.4 g. of 12a-methyl-1lot-hydroxyprogesterone in 10 ml. of pyridine and 0.5 ml. of mesyl chloride is kept at 0 for 16 hours. The solution is then diluted with iced water, the precipitated solid collected, washed well with water to give about 1.7 g. of the mesylate. Crystallization of a sample from acetonehexane furnishes an analytical sample having M.P. 172- 174 (dec.); [0:1 -+141 (c. 0.93 in CHCI W 238 mu 14,500) 5.91, 5.98, 6.22, 7.52

EXAMPLE 2 1 2 -M ethylene progesterone A solution of 1.58 g. of IZwmethyI-Ilot-hydroxyprogesterone lla-mesylate in 16 ml. of glacial acetic acid is heated under reflux with 1.6 g. of anhydrous sodium acetate for one hour. The mixture is diluted with water, and the steroids extracted with chloroform. The chloroform is washed several times with water, dried over sodium sulfate and the solvent removed in vacuo. The residue is taken up in 10 ml. of hexane-benzene (1:1) and absorbed on 30 g. of acid-Washed alumina. Flution with benzene (900 ml.) and with chloroform-benzene (1:9) (400 ml.) followed by crystallization from acetonehexane yields about 460 mg. of 12-methyleneprogesterone, M.P. -138; [@1 +168 (c. 1.19 in CHCI Nuiul ABM 24.0 111,417,200); ,W, 5.86, 6.00, 6.19;;

Analysis.Calcd. for C I-1 0 (326.46); C, 80.93; H, 9.26. Found: C, 81.34; H, 9.22.

Similarly, the lla-mesylates of IZoc-cthYl-lloa-hYdI'OXY- max.

progesterone and 12a-methyl-A -pregnadiene-l1a-ol-3,

20-dione can be converted to 12-ethylideneprogesterone and 12-methylene-A -pregnadiene 3,20-dione, respectively.

EXAMPLE 3 1 2-M ethylene-1 7a-Hydr0xypr0gester0ne Following the procedures of Examples 1 and 2 but substituting 1.6 g. of 12a-methyl-11u,17a-dihydroxyprogesterone for the 12a-methyl-1la-hydroxyprogesterone in the procedure of Example 1, there is obtained 12a-methyl- 11a,17a-dihydroxyprogesterone llu-mesylate and 12- methylene-A -pregnene-17a-ol-3,20-dione, respectively.

EXAMPLE 4 1 Z-Methyl- -Pregnene-1 1 06,21-DiUl-3,20'Di0ne l1 a-M esy late 21 -A cetate (a) Preparation of JZa-methyl A -pregnene-11u,21- diol-3,20-di0ne 21 -mon0acezate.A solution of 720 mg. of 12a-methyl-A -pregnene-1la,21-diol-3,20-dione in 10 m1. of pyridine and 220 mg. of acetic anhydride is kept at 0 for six hours. The solution is then concentrated in vacuo, the residue taken up in chloroform, and the solution extracted with dilute sulfuric acid, dilute bicarbonate 13 and water. Evaporation of thev solvent in vacuo leaves the monoacetate as a syrup, which is used in step b without further purification.

(12) Preparation of IZa-methyl A? pregame-111x31- dil-3,20-di0ne 11a-mesylate ZI-acetata-TO a solution of 804 mg. of IZa-rnethyl-M-pregnene-Ila,2l-diol 3,20- dione Zlmonoacetate in 10 ml. of anhydrous pyridine is added at 0, 0.4 ml. of meth anesulfonyl chloride. The mixture is allowed to remain at 0 for 18 hours. Ice is then added and the mixture extracted with chloroform. The chloroform extract is washed with dilute sulfuric acid, water, dilute bicarbonate and again with water, dried, and then evaporated to dryness in vacuo. The residue on crystallization from methanol gives the pure mesylate.

Similarly, by substituting the' anhydrides or acid chlorides of other acids in step av of Example 4, the corresponding Z-l-esters are formed. In this reaction the preferred acid anhydrides and acyl chlorides are those of hydrocarbon carboxylic acids having less than ten carbon atoms, asexemplified by the lower alkanoic acids (e.g., acetic, propionic and enanthic acid), the monocyclic aromatic c-arboxylic acids (e.g., benzoic and toluic acid), the monocyclic aralkanoic acids (e.g., phenacetic and B-phenylpropionic acid), the lower alkenoic acids, the cycloalkane carboxylic acids, and the cycloalkene carboxylic acids.

EXAMPLE 1Z-Methylene-M-Pregnene-ZI -Ol-3 ,2 O-Dione 21 -A aerate A solution of 500 mg. of IZu-methyl-M-pregnenella,2l-diol-3,20-dione lla-mesylate 21-acetate in ml. of glacial acetic acid is heated under reflux with 1.0 g. of anhydrous sodium acetate for one hour. The mixture is diluted with water, and the steroids extracted with chloroform. The chloroform extract is washed several times with water, dried over sodium sulfate and the solvent removed in vacuo. Crystallization of the resulting residue from acetone-hexane yields pure 12-methylene-A -pregnene-2l-ol-3,20-dione 21-acetate.

EXAMPLE 6 JZ-Methylene-M-Pregnene-Z1-Ol-3,20-Di0ne To a solution of 100 mg. of 1Z-methylene-M-pregnene- 21-ol-3,20-dione ZI-acetate in 12 ml. of methanol is added under nitrogen 0.207 ml. of an oxygen-free 10% aqueous solution of potassium carbonate. After 30 minutes at roomtemperature the mixture is neutralized with acetic acid and taken up in chloroform and water. The chloroform extract is dried over sodium sulfate and after evaporation in vacuo leaves lZ-methylene-Mpregnene-Z1-01- 3,2.0-dione, which is recrystallized from acetone-hexane.

Similarly, if lZea-methyl-A -pregnadiene-11a,21-di0l- 3,20-dione is substituted for the 12a-methyl-A -pregnenel la,21-diol-3,2O-d-ione in the procedure of Example 4 and the procedures of Examples 4, 5 and 6 are followed, 12amethyI-A -pregnadiene-I la,2l-d-iol3,20-dione ZI-acetate, 12a methyl-A -pregnadiene-llu,2ldiol-3,20-dione 110cmesylate ZI-acetate, 12a-methylene-A -pregnadiene-21- ol-3,20-dione 2l-acetate, and lZ-methylene-A -tpregn-adiene-21-o1-3,20 dione are formed, respectively. Furthermore, if other 12a-(1ower alkyl) steroid derivatives are substituted for the 12a-methyl steroid in Example 4, the corresponding 12a-(lower alkyl) steroids are formed.

EXAMPLE 7 1Z-Methylene-A -Pregnene-l 7 11,21 -Di0l-3,20-Di0ne Following the procedures of Examples 4, 5 and 6, but substituting 12amethyl-A -pregnene-11a,l7a,2l triol-3,20- dione for the 12a-methyl-A -pregnene-l1a,2-1-diol-3,20- dione in the procedure of Example 4, 12a.-methyl-A pregnene- 1la,17a,21-tr-iol-3,20-dione 21-acetate, 12amethyl-A pregnene-l1a,17a,2l-triol-3,2O-dione 11a mesylate ZI-acetate, IZ-methylene-M-pregnene-17a-2l-diol- 3,2 0 -dione ZI-acetate, and I Z-inethylenerM regnene 17a- 21-diol-3,20-dione are tormed, respectively. Similarly, other IZa-(lOWCI' alkyl) starting materials yield the corresponding l2-(lower alkylidene)derivatives.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimedis:

1. A compound selected from the group consisting of a steroid of the general formula and the 1,2-position unsaturate thereof, wherein R is lower alkylidene, Y is selected from the group consisting of hydrogen, hydroxy, and the acyloxy radical of a hydrocarbon canboxylic acid of less than ten carbon atoms, and Z is selected from the group consisting of hydrogen and hydroxy.

2. IZ-methylene progesterone.

3. IZ-methylene-M-pregnene-l7u.-ol-3,20-dione.

4. The 21-ester of 12-methylene-A -pregnene-3,ZO-dione-21-ol with a hydrocarbon carboxylic acid of less than ten carbon atoms.

5. The 21-e'ster of lZ-methylene-M-pregnene-l7a-21- diol-3,20-dione with a hydrocarbon canboxylic acid of less than ten carbon atoms.

6. A compound selected from the group consisting of a steroid of the general formula RSO20 CHgY' g i i and the 1,2-position unsaturate thereof, wherein R is lower alkylidene, Y is selected from the group consisting of hydrogen and the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms, and Z is selected from the group consisting of hydrogen and hydroxy, which comprises interacting a compound selected steroids of (lower alkyl) 2 (llHzY I i =0 i ---z RSOzO l:

9. The process of claim 8 wherein the steroid reactant is 12a-methyl-11ahydroxyprogesterone llwmesylate.

10. The process of claim 8 wherein the steroid reactant is 12a-methy1-11a.,17a-dihydroxyprogesterone lla-mesylate.

11. The process of claim 8 wherein the steroid reactant is IZa-methyl A pregnene-l1a,21-diol-3,20-dione 11amesylate 21-acetate.

12. The process of claim 8 wherein the steroid reactant is 12u methyl A pregnene-l1u,17u,21-triol-3,20-dione 1 l a-mesylate 21-acetate.

13. The process of claim 8 wherein an alkali metal acetate and acetic acid are employed in the reaction.

References Cited in the file of this patent UNITED STATES PATENTS 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A STEROID OF THE GENERAL FORMULA 